Living Textbook MC 417

Select Topic:

Sedatives, Hypnotics and Anxiolytics

A number of classes of drugs such as Barbiturates and Benzodiazepines are useful as sedatives, hypnotics and anti-anxiety drugs:

Pharmacology of Sleep:

Sleep was thought of as a passive process, until monitoring of human electrical brain activity (electroencephalogram = EEG) in the 1920s and 1930s showed that sleep has cycles of passive and wakeful activity.  These studies went on to show that there are two types of sleep, NREM (nonrapid eye movement) and REM (rapid eye movement). 

NREM makes up the majority of total sleep (75-80%), where dreaming is rare and muscles are not paralyzed.  It is divided into four stages that ends in deep sleep, but goes into cycles from stage 1 to stage 4, back into stage 1 and REM sleep and then the cycle continues.  Each cycle lasts for 90 - 120 min.  Various factors such as age affect sleep patterns.

There are a number of arousal pathways in the CNS.  These sites can be targeted by wake and sleep-promoting drugs.  Sleep is also controlled by different neurotransmitters (assumed to be involved in initiation or maintenance of REM sleep) and neurohumoral modulators.

Anxiety:

Anxiety is an unpleasant state of anticipation, apprehension, fear or dread.  It has both physiological and psychological symptoms.  There are a wide range of anxiety Disorders, including panic disorder, agoraphobia, generalized anxiety disorder, social phobia/performance anxiety, specific phobia, posttraumatic stress disorder and obsessive compulsive disorder.  

Benzodiazepines

Benzodiazepines (BZDs) act by binding to their own receptor site on the GABAA receptor, resulting in an increase in the binding of GABA and ultimetiley eliciting more Clchannel openings.  The pharmacological effects of BZD, as with many other related agents, are dose dependent, and they are therapeutically useful in a wide variety of indications that rely on their CNS depressant effects.  These agents have anxiolytic activity, can be used for their sedative effect as well as showing skeletal muscle relaxation and anticonvulsive activity.  Many of these agents also cause anterograde amnesia.

Pharmacokinetics of BZDs

The pharmacokinetics of BZDs are primarily responsible for the variability of clinical effects seens with the different agents in this drug class.  They all have different rates of absorption, metabolism and excretion and this leads to varying clinical properties and subsequently how they are prescribed.  For example, agents with greater lipid solubility leads to greater absorption and more rapid onset of action.  Their elimination half-life, which is determined largely by metabolism, since many of the agents produce active metabolites.  Highly lipophilic agents are more likely to enter the CNS rapidly, but their duration of action will rely heavily on their redistribution out of the CNS.  This is due to the fact that their therapeutic effects is due solely to their CNS actions.  For example, Diazepam will have a very short duration of action despite having a long elimination half-life, since it is highly lipophilic and will be redistributed out of the CNS rapidly, while Lorazepam shows a slower onset, but a longer duration of action since it is more water soluble and thus redstributes out of the brain slower.

Indications for BZDs:
Therapeutic uses and pharmacological effects of BZDs depend largely on their half life and binding to receptor subtypes. 

For anticonvulsants, a long half life and rapid entry into the CNS is preferred, especially for status epilepticus.  For hypnotics, a short elimination half-life fis desired, while anxiolytics should have longer half life.

Most BZDs bind to the different receptor subtypes.  Sedation and anticonvulsant effect is mainly mediated via the α1 subtype, anxiolytic effect via α2 subtype, while anesthetic action is more pronunced via binding to β2 and β3 subtypes.

Structure Activity Relationship

There are two types of BZDs, class I and class II.  Class II has an extra ring attached to the seven-membered ring. 

These agents have two enantiomeric isomers, an R and an S, but they are available commercially as the racemic mixture.

Position 1, substitution with small alkyl groups will retain activity, while larger groups, such as t-butyl will decrease activity due to steric hinderness.

Position 2, a hydrogen bond acceptor is a must, for binding with the receptor.  Replaceing the oxygen with a sulfur may affect selectivity.

Position 3, a hydroxyl or ester substitution will retain activity.

The double bond between Position 4 and 5 could be reduced and retain in vivo activity.

Position 5, Substitution is not essential, but may provide interaction with the receptor.  While ortho-substitution is tolerated, para-substitution will lower activity due to steric hinderness.

Position 7, and electron-withdrawing group increases activity.

Posiitions 6, 8 and 9 substitutions are not tolerated.

An aromatic ring A is essential for binding with the receptor.

Drug-Drug Interactions

Side Effects

  • Lightheadedness and increased reaction time
  • Motor uncoordination, drowsiness and confusion especially with drugs with long t1/2
  • Rebound withdrawal effects: rebound anxiety or wakefulness, especially with drugs with short t1/2 or abrupt discontinuation of the drug
  • Ataxia and nystagmus
  • Anterograde amnesia
  • Paradoxical excitement

BZDs should be given at night to avoid many of these unwanted effects.  As with many CNS depressants, they should not be combined with alcohol as it would potentiate some of these unwanted effects.

Containdications

  • Avoid BZDs in COPD and obstructive sleep apnea patients, as they may decrease muscular tone in upper airway
  • Avoid use in alcoholics and older patients with liver problems.  Older patients can use BZDs not metabolized by CYP450

Tolerance, Abuse and Dependence

Abuse is less of a problem than other hypnotics, but is usually   seen in abusers of other substances.

Physical dependence is seen after long-term use.

Individual Agents:

Alprazolam (Xanax®) - Top 200 Drug

Class B BZD, indicated in anxiety and panic disorder.  It is a relatively short acting agent, and is often abused.

Clonazepam (Klonopin®) - Top 200 Drug

Class A BZD, indicated in anxiety, panic disorder as well as non-labeled use such as restless leg syndrome.  It has a relatively long duration of action.

Clorazepate (Tranxene®)

Class A BZD, an anxiolytic and anticonvulsant agent has an unusual carboxylic acid.  It is decarboxylated to the desmethyldiazepam, that is responsible for most of the activity.

Diazepam (Valium®) - Top 200 Drug

Class A BZD, with a fast onset (0.5-2 hrs peak plasma time), short duration of action and a long elimination half-life (30-60 hours).  It has a wide variety of use including as an anticonvulsant, muscle relaxant and an anxiolytic agent.

Estazolam (ProSom®)

Class B BZD, an intermediate-acting agent, used in short term management of insomnia.

Flurazepam (Dalmane®)

Class A BZD, is rapidly absorbed and has a long duration of action.  It forms active metabolites, leading to the potential of dependence.  It is metaboized via hydroxylationa nd glucurodination or N-dealkylation.  It is mostly used as a hypnotic.

Halazepam (Paxipam®)

Class A BZD that is no longer available in the US.

Lorazepam (Ativan®) - Top 200 Drug

Class A BZD, with an intermediate onset (1-6 hrs peak plasma time), intermediate duration of action and elimination half-life (10-18 hours).  It is mostly used in anxiety disorders.

Midazolam (Versed®)

Class B BZD, used by IV or IM injections, has
a short duration of action and elimination half-life (2-5 hours), as it is rapidly inactivated. Its oral formulation (syrup) should only be used in hospital settings due to the potential for respiratory depression.

Oxazepam (Serax®)

Class A BZD, an intermediate acting agent, used in anxiety and in alcohol withdrawal.

Temazepam (Restoril®) - Top 200 Drug

Class A BZD, an agent used for short term insomnia, shows slow absorption (2-3 hours plasma peak time), so should be given 1-2 hours before bedtime, but does vary depending on drug dosage form, with the soft gelatin capsule causing lower sleep induction and better sleep maintainance.

Triazolam (Halcion®)

Class B BZD, has an relatively fast onset (1-2 hrs peak plasma time), short duration of action and elimination half-life (1.5-4 hours).  It is used for short term treatment of insomnia, and causes amnesia at high doses.

Related Agent:

Flumazenil (Romazicon®) is a BZD receptor antagonist that will reverse the actions of BZD and when used intravenously, will help recovery from their sedating or anesthetic effects, and may be used in cases of overdosing on BZDs.